Hot flashes pose a significant public heath problem because they are the most common perimenopausal symptom reported by women in the United States and the primary reason that women seek medical care during the menopausal transition. Despite the public health importance of hot flashes, little is known about the factors that predispose women to hot flashes. During the previous funding period, new preliminary data were obtained that indicate that obesity increases the risk of perimenopausal hot flashes. Thus, the overall goal of this renewal application is to examine the mechanism by which obesity increases the risk of hot flashes. Specifically, the proposed work will test the hypothesis that obesity is associated with hot flashes through mechanisms that involve early ovarian failure, altered sex steroid hormone levels, and selected genetic polymorphisms in steroidogenic enzymes and steroid hormone receptors. The specific aims are to determine whether: 1) obesity is associated with early ovarian follicle loss and altered levels of sex steroid hormones, 2) obesity is associated with selected polymorphisms in genes that encode enzymes that synthesize and degrade sex steroids and/or receptors that respond to sex steroids, 3) selected polymorph- isms are associated with sex steroid hormone levels, and 4) the association between obesity and hot flashes is mediated by early ovarian follicle loss, altered hormone levels, and/or selected genetic polymorphisms. To complete these aims, obese and non-obese perimenopausal women with and without hot flashes will complete questionnaires, receive transvaginal ultrasounds for measurement of ovarian volume and follicle numbers, and provide blood samples for measurement of selected sex steroid hormones and genetic polymorphisms in steroidogenic enzymes and steroid hormone receptors. Ovarian volume, follicle numbers, sex steroid hormone levels, and the odds of having selected genetic polymorphisms will be compared in obese and non-obese women using appropriate statistical tests. Further, statistical models will be used to determine whether the association between obesity and hot flashes is attenuated by adjustment for ovarian volume, follicle numbers, sex steroid hormone levels, and selected genetic polymorphisms. The results of this study will provide information about risk factors for perimenopausal hot flashes. In turn, this information may be useful for the future development of novel strategies to prevent or treat hot flashes. [unreadable] [unreadable] [unreadable]